Musculoskeletal and connective tissue inflammations are common diseases affecting a large human population. Some commonly seen musculoskeletal and connective tissue inflammations include osteoarthritis and associated articular and periarticular inflammations, and non-articular Rheumatism including capsulitis, tendonitis, fibrositis, and periarticular inflammations.
Osteoarthritis is the most common type of arthritis, especially among older people. Osteoarthritis is a joint disease that mostly affects the cartilage. Cartilage is the slippery tissue that covers the ends of bones in a joint. Healthy cartilage allows bones to glide over one another. It also absorbs energy from the shock of physical movement. In osteoarthritis, the surface layer of cartilage breaks down and wears away. This allows bones under the cartilage to rub together, causing pain, swelling, and loss of motion of the joint. Over time, the joint may lose its normal shape. Also, bone spurs may grow on the edges of the joint. Bits of bone or cartilage can break off and float inside the joint space. This causes more pain and damage. People with osteoarthritis usually have joint pain and limited movement. Unlike some other forms of arthritis, osteoarthritis only affects joints, and not internal organs.
Osteoarthritis is one of the most frequent causes of physical disability among adults. More than 20 million people in the United States probably have the disease. Some younger people get osteoarthritis from a joint injury, but osteoarthritis most often occurs in older people. In fact, by age 65, more than half of the population has x-ray evidence of osteoarthritis in at least one joint. Since the number of older Americans is increasing, so is the number of people with osteoarthritis. Both men and women have the disease.
Existing osteoarthritis treatment approaches include exercise, medicines, rest and joint care, surgery, pain relief techniques, alternative therapies, and weight control. The commonly used medicines in treating osteoarthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), for example, aspirin, Advil® (ibuprofen), Motrin® IB (ibuprofen), Aleve® (naproxen sodium), ketoprofen; topical pain-relieving creams, rubs, and sprays (for example, capsaicin cream) applied directly to the skin; corticosteroids, powerful anti-inflammatory hormones made naturally in the body or man made for use as drugs, typically injected into affected joints to relieve pain temporarily; and hyaluronic acid, a new medicine for joint injection, used to treat osteoarthritis of the knee. Surgery may be performed to resurface (smooth out) bones, reposition bones, and replace joints. For some people, surgery helps relieve the pain and disability of osteoarthritis. Osteoarthritis is a chronic disease. Although various medications have been used for treating the disease, they are not effective for long term control and prevention.
One of most common forms of capsulitis is adhesive capsulitis, also referred as “frozen shoulder”, a painful condition which results in a severe loss of motion in the shoulder. The symptoms are primarily pain and a reduced range of motion in the joint due to the severe inflammation of the joint capsule. The shoulder usually hurts when movement reaches the limit of the range of motion, and can be quite painful at night. The cause of this condition is not clear. One theory is that the condition may be due to an autoimmune reaction. Adhesive capsulitis may begin following other injuries where the shoulder is not moved around normally because of the other injury. A common example is after a wrist fracture the arm may be kept in a sling for several weeks, which limits the shoulder movement. In addition, the frozen shoulder condition can begin while other shoulder problems are present. Sometimes, problems such as bursitis, impingement syndrome, or a partial rotator cuff tear can lead to a frozen shoulder as well.
Usually, the adhesive capsulitis must be treated first to regain motion in the shoulder before the underlying problem can be addressed. Treatment of the frozen shoulder can be frustrating and slow. Initial treatment is directed at decreasing inflammation and increasing the range of motion of the shoulder with a stretching program. Anti-inflammatory medications can be used. It is important that a physical therapy program be started and continued to regain the loss of motion. An injection of cortisone and long-acting anesthetic may bring the inflammation under better control, and allow the stretching program to be more effective. Most cases will eventually improve, but it is common that the range of motion is not fully recovered.
Tendonitis is an inflammatory condition characterized by pain at tendinous insertions into bone. Common sites of tendonitis include rotator cuff of the shoulder (supraspinatus and bicipital tendons); insertion of the wrist extensors (lateral epicondylitis and tennis elbow) and flexors (medial epicondylitis) at the elbow; patellar and popliteal tendons and iliotibial band at the knee; insertion of the posterior tibial tendon in the leg (shin splints); and achilles tendon at the heel. Tendonitis most commonly is caused by overuse. Pathologic changes consistent with chronic inflammation usually are observed. Tissue degeneration, characterized by cell atrophy, also may be observed. Calcium can deposit along the course of the tendon (ie, calcific tendinitis), with the shoulder being the most common site. Chronic tendonitis can lead to weakening of the tendon and subsequent rupture. Middle-aged adults are most susceptible to the development of tendonitis.
The goals of pharmacotherapy in treating tendonitis are to control pain and decrease inflammation. Existing treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), splinting or immobilization; and peritendinous lidocaine/corticosteroid injection. Nonsteroidal anti-inflammatory drugs include, ibuprofen, flurbiprofen, naproxen, mefenamic acid, ketoprofen, indomethacin, and piroxicam.
Fibrositis is a relatively common form of nonarticular rheumatism. Fibrositis can be localized or diffuse. The diffuse fibrositis, occurring at multiple locations of the body is also called fibromyalgia. Fibrositis and fibromyalgia are disorders associated with pain and tenderness of muscle and adjacent connective tissue, which indicate pain in fibrous tissues, muscles, tendons, ligaments, and other sites. Any fibromuscular tissues may be involved, but those of the occiput, neck, shoulders, thorax, low back and thighs are especially affected. For fibromyalgia various focal “trigger points” of tenderness can be identified, and systemic symptoms such as fatigue, insomnia, and depression are frequently present.
The pain and sore spots characteristic of fibrositis can be due to several causes. First, there may be a local inflammation due to a virus. This is like having a “cold” in your back or neck. Generalized muscle pains may be due to systemic toxins in the blood that results from a viral infection, usually somewhere else other than in the aching muscles or joint capsules. Further, one common cause of localized tender spots is what is called “referred pain”. A common site of inflammation due to trauma, such as a strain or a sprain, is in the many joints in connection with the spine. Because these joints are close to the coverings of the nerves being distributed from the spinal cord, the covering of these nerves called the “dura” may become irritated or inflamed. When this happens, the trouble is not where it hurts, but deeper inside around the inflamed joint linings and nerve coverings. If the pain and tenderness last for more than a few months, then chronic pain and joint stiffness can result. The above described mechanism occurs in many different body sites. The elbow, heel, back, neck, and shoulder associated with painful tender spots are common locations. The existing treatments for fibrositis include cortisone injection, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical therapies. For fibromyalgia, the treatments also include tricyclic antidepressants for relaxing muscles and improving quality of sleep, exercise and self-relaxation.
Many of the musculoskeletal and connective tissue inflammations are chronic and cause chronic regional pain and loss of functionality of affected areas. These diseases can hurt people more than physically. Their finances and lifestyles are also affected. Financial effects include the cost of treatment, and wages lost because of disability. Lifestyle effects include depression, anxiety, feelings of helplessness, limits on daily activities, job limitations, and loss of everyday family joys and responsibilities.
13-cis retinoic acid, more generally known as retinoic acid, also referred to as isotretinoin, and sold under the trademark Accutane® from Hoffmann-La Roche Inc., Nutley, N.J., has long been known as a topical and oral dermatological agent used in the treatment of acne vulgaris and several other skin diseases. 13-cis retinoic acid inhibits sebaceous gland function and keratinization. The exact mechanism of action of Accutane® in treating acne is unknown. Since retinoic acid is a teratogenic drug and, because of the mutagenic effects associated with such drugs, it is only used for treating severe acne vulgaris when other treatments are not effective.
Since 1992 there have been literature reports on the potential effect of 13-cis-retinoic acid upon human prostate cancer cells. U.S. Pat. No. 5,612,354 (to Sanz et al) discloses a method of treating mammals suffering from disorders which are characterized by an increased proliferation or abnormal differentiation of cells by the systemic or topical administration to the mammals of an effective amount of (1H-azol-1-ylmethyl) substituted quinoline derivatives, including 13-cis-retinoic acid. It is believed that because of the capability to delay the metabolism of retinoic acid, (1H-azol-1-ylmethyl) substituted quinoline derivatives may potentially be used in treating cancers.
As described above, it is apparent that there still is a strong need for medications that can effectively treat musculoskeletal and connective issue inflammations. A medication that can provide a long term control of musculoskeletal and connective tissue inflammations, inhibit further progress of existing conditions, and prevent reoccurrence of acute symptoms will have important medical significance for millions of people who suffer from these diseases.